CD146 as a potent target for anti-vascular therapies in lung cancer brain metastasis

Tumors in brain are hype-angiogenic and the anti-vascular therapies are important for the treatment of non-small cell lung carcinoma (NSCLC) derived brain metastasis (BM). Targeting vascular endothelial growth factor (VEGF) and its receptor (VEGFR) is the most effective way of resisting angiogenesis. However, the most widely-used anti-vascular drug (Bevacizumab, Bev) has limited therapeutic effects on NSCLC BM. Here, we defined the overexpression of CD146 and its potent pro-angiogenesis role in NSCLC BM in clinical samples, animal models and ex vivo bionic microfluidic chips. Mechanistically, CD146 exerts a comprehensive and sustained reinforcing effect on the pro-angiogenic VEGF-VEGFR2 axis on the one hand by up-regulating tumoral VEGF transcription and on the other hand by amplifying and sensitizing the VEGFR on endothelial cell as a co-receptor. By revealing the underlying mechanism by which CD146 upregulated in BM that the reactive astrocyte-derived growth arrest specific 6 (GAS6) induces the transcription of CD146 by activating AXL signaling, we demonstrated Bemcentinib (R428/BGB324), an AXL inhibitor, effectively suppressed the CD146 expression in BM cells and exhibited superior anti-vascular efficacy against brain metastases when used alone and in combination with Bev in vivo, providing novel anti-vascular strategies in BM.